The present invention concerns novel multicomponent crystals of ([2-amino-6-(4-fluoro-benzylamino)-pyridin-3-yl] carbamic add ethyl ester and 2-[2-[(2,6-dichlorophenyl)-amino]-phenyl] acetic add, their manufacture as well as their use in pharmaceutical preparations. The multicomponent crystals according to the invention are suitable for treatment of pain conditions, in particular of unclear genesis, by a simultaneous action on pains that are caused by muscle tension or degenerative joint diseases as well as on those that are caused by inflammatory processes.
([2-amino-6-(4-fluoro-benzylamino)-pyridin-3-yl] carbamic acid ethyl ester, also known as flupirtine, is a centrally acting non-opioid analgesic agent that is free of the typical side effects of natural or synthetic opioids such as, for example, respiratory depression, constipation, development of drug tolerance, physical or psychological dependence or risk of addiction, Flupirtine is an active ingredient that can normalize an increased muscular tone.
Flupirtine is the prototype of a new class of analgesics with new specific and therapeutically relevant properties. In this context, the mode of action of flupirtine is not based on a direct but on an indirect functional NMDA antagonistic effect. This mechanism results in three different action principles: analgesic, muscular tone-reducing, and neuroprotective. The various actions of flupirtine are the result of a single molecular action mechanism, i.e., the action of flupirtine as a selective neuronal potassium channel opener (selective neuronal potassium channel opener=SNEPCO) (see, for example, Kornhuber J et al. (1999); Kornhuber J et al. (1999a)) that represents a new principle in pain therapy.
As a result of these multiple actions, flupirtine exhibits a unique and broad pharmacological action spectrum. Flupirtine is suitable for treatment and prophylaxis of acute and chronic pain, including neuropathic pain, nerve pain, pain caused by cancer diseases, vasomotoric and migraine headaches, pain conditions after operations, after injuries, burns, in case of dysmenorrhea, toothache and arthritic pain.
Anti-inflammatory effects of flupirtine are to be expected for conventional analgesic dosages only to a minimal degree because a significant anti-inflammatory action has been observed in animal experiments only upon very high dosages (>30 mg per kg body weight). Flupirtine is primarily effective in the treatment and prophylaxis of pains that in particular are caused by muscle tension, muscle spasms and muscle stiffness. It is particularly effective for the treatment of back pain wherein a clear differentia diagnosis regarding the genesis of this tension-caused back pain in the meaning of inflammatory and/or non-inflammatory causes cannot always be determined unequivocally in an individual case.
Flupirtine maleate can be combined with various pain relievers, for example, with morphine (EP 0977736), with neurokinin antagonists (WO 2007/128056) with tramadol (EP 1697005) or also paracetamol (EP 207 193).
2-[2-[(2,6-dichlorophenyl)-amino]-phenyl] acetic acid (diclofenac) belongs to the group of non-steroidal antirheumatic substances (NSAIDS). They inhibit non-selectively the cyclooxygenases (COX) I and II which are responsible in the organism for the generation of inflammation-mediating prostaglandins.
Diclofenac is a pharmaceutical substance that is used as a sodium or potassium salt in case of light to medium pain and inflammation, for example, in case of rheumatism, contusions, strain traumata, and arthrosis. Chemically, it belongs to the phenyl acetic adds. Diclofenac exhibits antipyretic, analgesic, antiphlogistic and anti-rheumatic effectiveness.